Binding of the Radioligand SIL23 to a-Synuclein Fibrils in Parkinson Disease Brain Tissue Establishes Feasibility and Screening Approaches for Developing a Parkinson Disease Imaging Agent

Accumulation of a-synuclein (a-syn) fibrils in Lewy bodies and Lewy neurites is the pathological hallmark of Parkinson disease (PD). Ligands that bind a-syn fibrils could be utilized as imaging agents to improve the diagnosis of PD and to monitor disease progression. However, ligands for a-syn fibrils in PD brain tissue have not been previously identified and the feasibility of quantifying a-syn fibrils in brain tissue is unknown. We report the identification of the 125I-labeled a-syn radioligand SIL23. [125I]SIL23 binds a-syn fibrils in postmortem brain tissue from PD patients as well as an a-syn transgenic mouse model for PD. The density of SIL23 binding sites correlates with the level of fibrillar a-syn in PD brain tissue, and [125I]SIL23 binding site densities in brain tissue are sufficiently high to enable in vivo imaging with high affinity ligands. These results identify a SIL23 binding site on a-syn fibrils that is a feasible target for development of an a-syn imaging agent. The affinity of SIL23 for a-syn and its selectivity for a-syn versus Ab and tau fibrils is not optimal for imaging fibrillar a-syn in vivo, but we show that SIL23 competitive binding assays can be used to screen additional ligands for suitable affinit